Changes in cardiomyocyte size occur in a variety of clinical scenarios, including pressure overload, myocardial infarction, metabolic stress, and in some genetic conditions. Although much is now known about the signaling pathways that cause cardiomyocytes to hypertrophy, much less is known about the pathways that inhibit or reverse hypertrophy, nor do we understand how cardiomyocytes atrophy in conditions such as dilated cardiomyopathy. At the molecular level, almost nothing is known about how cardiac proteins such as sarcomere components are removed to accommodate reductions in cell size. These unanswered questions represent a major gap in our understanding of the pathophysiology of cardiovascular disease. Our laboratory has recently identified 2 ubiquitin ligases, atrogin and MuRF1 (muscle ring-finger protein 1), that are responsible for antagonizing cardiomyocyte signaling in the setting of hypertrophic stress, in part through targeted degradation of cardiomyocyte signaling and structural proteins. These proteins therefore provides ideal models for understanding how cardiomyocytes adapt to stress and how cell size is regulated and maintained in pathophysiologic circumstances. We hypothesize that cardiac-specific ubiquitin ligases play key roles in antagonizing cardiomyocyte signaling pathways that provoke hypertrophy, and regulate adaptive responses in the setting of cardiomyocyte stress. Knowledge of the regulation of these proteins and how they affect specific signaling events and choose targets for ubiquitylation will provide a new level of understanding of how the heart responds to clinically relevant insults. To test these hypotheses, we propose a combined biochemical, cellular, genetic, and physiologic approach 1) to characterize the cellular relationships between atrogin and cardiac growth pathways in mediating responses to stress;2) To assess the molecular and cellular roles of MuRF family proteins in cardiomyocyte stress responses;and 3) To contrast the roles of MuRFs 1-3 in pathophysiologic cardiac responses. In addition to providing a new basis to appreciate the role of targeted protein turnover as a key regulatory mechanism in cardiomyocyte biology, these studies will help us to predict whether these proteins represent new potential targets for intervention in diseases associated with abnormal regulation of cardiomyocyte volume.